Phase Ib dose-escalation study of the hypoxia-modifier Myo-inositol trispyrophosphate in patients with hepatopancreatobiliary tumors

• DOI: 10.1038/s41467-021-24069-w
• Publication Date: 2021-06-21T10:03:10Z
• Authors: Marcel A. Schneider; Michael Linecker; Ralph Fritsch; Urs J. Muehlematter; Daniel Stocker; Bernhard Pestalozzi; Panagiotis Samaras; Alexander Jetter; Philipp Kron; Henrik Petrowsky; Claude Nicolau; Jean-Marie Lehn; Bostjan Humar; Rolf Graf; Pierre-Alain Clavien; Perparim Limani
• Keywords: Male; Science; Inositol Phosphates; 610 Medicine & health; 1600 General Chemistry; Digestive System Neoplasms; Article; 03 medical and health sciences; 0302 clinical medicine; 1300 General Biochemistry, Genetics and Molecular Biology; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Humans; Hypoxia; 10217 Clinic for Visceral and Transplantation Surgery; Aged; 10042 Clinic for Diagnostic and Interventional Radiology; Q; Liver Neoplasms; Middle Aged; 3100 General Physics and Astronomy; Progression-Free Survival; 3. Good health; 10199 Clinic for Clinical Pharmacology and Toxicology; 10032 Clinic for Oncology and Hematology; Administration, Intravenous; Female; Colorectal Neoplasms

AbstractHypoxia is prominent in solid tumors and a recognized driver of malignancy. Thus far, targeting tumor hypoxia has remained unsuccessful. Myo-inositol trispyrophosphate (ITPP) is a re-oxygenating compound without apparent toxicity. In preclinical models, ITPP potentiates the efficacy of subsequent chemotherapy through vascular normalization. Here, we report the results of an unrandomized, open-labeled, 3 + 3 dose-escalation phase Ib study (NCT02528526) including 28 patients with advanced primary hepatopancreatobiliary malignancies and liver metastases of colorectal cancer receiving nine 8h-infusions of ITPP over three weeks across eight dose levels (1'866-14'500 mg/m2/dose), followed by standard chemotherapy. Primary objectives are assessment of the safety and tolerability and establishment of the maximum tolerated dose, while secondary objectives include assessment of pharmacokinetics, antitumor activity via radiological evaluation and assessment of circulatory tumor-specific and angiogenic markers. The maximum tolerated dose is 12,390 mg/m2, and ITPP treatment results in 32 treatment-related toxicities (mostly hypercalcemia) that require little or no intervention. 52% of patients have morphological disease stabilization under ITPP monotherapy. Following subsequent chemotherapy, 10% show partial responses while 60% have stable disease. Decreases in angiogenic markers are noted in ∼60% of patients after ITPP and tend to correlate with responses and survival after chemotherapy.